Reacción a ""Promising" new strategy for ALS using stem cells created from patients"

The recently published work by Landry et al. focuses on a familial form of amyotrophic lateral sclerosis (ALS), the most common form in Brazil, using motor neuron models derived from human iPSCs [induced pluripotent stem cells]. It is a classic and robust study, cleverly using genetic methods to study the effect on motor neurons of the mutated protein in patients, VAPB, in its ‘healthy’ or mutated (P56S) form associated with ALS type VIII. In general, the conclusions are well supported by solid data including functional, molecular and morphological analyses, as well as phenotypic rescue through pharmacological inhibition of the integrated stress response (ISR).

Among the pathological phenotypes observed in motor neurons expressing only the mutant form are a reduction in the endoplasmic reticulum-mitochondrial connection, a reduction in mitochondrial membrane potential, and a reduction in motor neuron electrical activity. The authors coherently integrate existing evidence on the role of VAPB in the connection between the endoplasmic reticulum and mitochondria and the emerging role of ISR in neurodegeneration. The novelty of the study is the direct association it makes between mutation-specific mitochondrial dysfunction, due to reduced contact with the endoplasmic reticulum, and increased activation of ISR. Some of these phenotypes (not the electrophysiological one) have also been observed in motor neurons derived from iPSCs obtained from patients (with the mutation in heterozygosity) compared to controls where the mutation is genetically corrected. This corroborates that these defects can also occur in patients.

It remains to be understood how, mechanistically, the reduction in contact between the endoplasmic reticulum and mitochondria caused by the mutation generates greater stress in these compartments, leading to higher ISR activation. In fact, the role of ISR in ALS has been studied in recent years in multiple familial forms of the disease. According to the authors of the study, it appears that, in different forms of ALS, elevated ISR activation may have both positive and negative effects. Therefore, the use of drugs that modulate this pathway upwards or downwards will depend on the type of ALS patient. In fact, two clinical trials cited in the article, which enhance ISR activation, have already failed in the early stages.

Among the limitations, it is recognised that the results focus on a specific genetic subtype of ALS, which represents a very low percentage of patients (<1%), thus limiting immediate generalisation to other subtypes. Furthermore, although phenotypic reversal is demonstrated with an ISR pathway inhibitor, it is not fully explored whether treatment can halt or reverse neuronal degeneration in advanced stages.

The clinical implications are clear: this work supports the stratified treatment of ALS based on patient genetics and proposes ISR modulation as a viable therapeutic target in specific subgroups. This is particularly relevant following the failure of clinical trials with ISR inhibitors in unstratified populations. Furthermore, it should be studied in depth how these treatments can correct motor neuron degeneration without affecting how the rest of the body's cells deal with cellular stress.